It has been estimated that there is a 42% chance for a 50 year-old American to develop histologically recognizable prostate cancer, and in 1991 cancer of the prostate surpassed lung cancer as the most commonly diagnosed cancer in U.S. males, becoming the second leading cause of death. The lifetime risks for being diagnosed with clinical prostate cancer is 9.5% and of dying from the cancer 2.9%. Clearly, development of an understanding of the genetic/biochemical abnormalities leading to prostate cancer methods for treatment of the cancer are required. At the present time, existing animal models for studying the development of prostate cancer are chiefly inbred rat strains that typically required administration of hormones and/or carcinogens for cancer development, and mice expressing T antigen or ras and myc oncogenes. Generally, the tumors are not representative of cancers seen in humans. To rectify this situation, Dr. Norris has proposed to develop mouse models of prostate cancer with prostate-targeted expression of a restriction enzyme, the c-fos proto-oncogene, or a modified nuclear lamin, all molecules predicted to induce genetic instability. Specific aim #1 will be to develop founder strains of mice expressing either the retrotransposon (RTP) or the genome destabilizing transgenes. Specific aim #2 will be to crossbreed founder strains to RTP mice, and in some cases to p53 (-/-) null mice, to create strains that have early or late developing prostate cancer. Specific aim #3 will be to evaluate the prostate cancer at the genetic, biochemical, and cellular level in order to establish the relationship of mouse tumors to human prostate cancer. Assays that will be carried out include karyotyping, analysis of retrotransposon and microsatellite stability as a monitor for genomic instability, biochemical analyses of indicator genes expected to be aberrantly expressed in tumors and to determine androgen responsiveness of induced tumors. In conclusion, prostate cancer in humans is projected to increase significantly in the next 15 years, making this proposal timely. Dr. Norris and coworkers will focus on developing an animal model with well-characterized genetics where realistic studies can be undertaken that have a higher probability of developing and understanding of molecular events associated with the disease process, and accomplishing this group's future plan of a rational gene therapy interventional approach for clinical treatment.